Skip to main content

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adjuvant Colon Cancer

Table 4 shows the adverse reactions occurring in ≥ 5% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment. A total of 995 patients were treated with 1250 mg/m² twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 974 patients were administered 5-FU and leucovorin (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5FU on days 1-5 every 28 days). The median duration of treatment was 164 days for capecitabinetreated patients and 145 days for 5-FU/LV-treated patients. A total of 112 (11%) and 73 (7%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions. A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV.

Table 5 shows grade 3/4 laboratory abnormalities occurring in ≥ 1% of patients from one phase 3 trial in patients with Dukes' C colon cancer who received at least one dose of study medication and had at least one safety assessment.

Table 4 : Percent Incidence of Adverse Reactions Reported in ≥ 5% of Patients Treated With XELODA or 5-FU/LV for Colon Cancer in the Adjuvant Setting (Safety Population)

Body System/Adverse Event Adjuvant Treatment for Colon Cancer
(N=1969)
XELODA
(N=995)
5-FU/LV
(N=974)
All Grades Grade 3/4 All Grades Grade 3/4
Gastrointestinal Disorders
  Diarrhea 47 12 65 14
  Nausea 34 2 47 2
  Stomatitis 22 2 60 14
  Vomiting 15 2 21 2
  Abdominal Pain 14 3 16 2
  Constipation 9 - 11 < 1
  Upper Abdominal Pain 7 < 1 7 < 1
  Dyspepsia 6 < 1 5 -
Skin and Subcutaneous Tissue Disorders
  Hand-and-Foot 60 17 9 < 1
  Syndrome
  Alopecia 6 - 22 < 1
  Rash 7 - 8 -
  Erythema 6 1 5 < 1
General Disorders and Administration Site Conditions
  Fatigue 16 < 1 16 1
  Pyrexia 7 < 1 9 < 1
  Asthenia 10 < 1 10 1
  Lethargy 10 < 1 9 < 1
Nervous System Disorders
  Dizziness 6 < 1 6 -
  Headache 5 < 1 6 < 1
  Dysgeusia 6 - 9 -
Metabolism and Nutrition Disorders
  Anorexia 9 < 1 11 < 1
Eye Disorders
  Conjunctivitis 5 < 1 6 < 1
Blood and Lymphatic System Disorders
  Neutropenia 2 < 1 8 5
Respiratory Thoracic and Mediastinal Disorders
  Epistaxis 2 - 5 -

Table 5 : Percent Incidence of Grade 3/4 Laboratory Abnormalities Reported in ≥ 1% of Patients Receiving XELODA Monotherapy for Adjuvant Treatment of Colon Cancer (Safety Population)

Adverse Event XELODA
(n=995)
Grade 3/4 %
IV 5-FU/LV
(n=974)
Grade 3/4 %
Increased ALAT (SGPT) 1.6 0.6
Increased calcium 1.1 0.7
Decreased calcium 2.3 2.2
Decreased hemoglobin 1.0 1.2
Decreased lymphocytes 13.0 13.0
Decreased neutrophils* 2.2 26.2
Decreased neutrophils/granulocytes 2.4 26.4
Decreased platelets 1.0 0.7
Increased bilirubin** 20 6.3
*The incidence of grade 3/4 white blood cell abnormalities was 1.3% in the XELODA arm and 4.9% in the IV 5FU/LV arm.
**It should be noted that grading was according to NCIC CTC Version 1 (May, 1994). In the NCIC-CTC Version 1, hyperbilirubinemia grade 3 indicates a bilirubin value of 1.5 to 3.0 × upper limit of normal (ULN) range, and grade 4 a value of > 3.0 × ULN. The NCI CTC Version 2 and above define a grade 3 bilirubin value of > 3.0 to 10.0 × ULN, and grade 4 values > 10.0 × ULN.

Metastatic Colorectal Cancer

Monotherapy

Table 6 shows the adverse reactions occurring in ≥ 5% of patients from pooling the two phase 3 trials in first line metastatic colorectal cancer. A total of 596 patients with metastatic colorectal cancer were treated with 1250 mg/m² twice a day of XELODA administered for 2 weeks followed by a 1-week rest period, and 593 patients were administered 5-FU and leucovorin in the Mayo regimen (20 mg/m² leucovorin IV followed by 425 mg/m² IV bolus 5-FU, on days 1-5, every 28 days). In the pooled colorectal database the median duration of treatment was 139 days for capecitabine-treated patients and 140 days for 5-FU/LV-treated patients. A total of 78 (13%) and 63 (11%) capecitabine and 5-FU/LV-treated patients, respectively, discontinued treatment because of adverse reactions/intercurrent illness. A total of 82 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 50 (8.4%) patients randomized to XELODA and 32 (5.4%) randomized to 5-FU/LV.

Table 6 : Pooled Phase 3 Colorectal Trials: Percent Incidence of Adverse Reactions in ≥ 5% of Patients

Adverse Event XELODA (n=596) 5-FU/LV (n=593)
Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 %
Number of Patients With > One Adverse Event 96 52 9 94 45 9
Body System/Adverse Event
GI
  Diarrhea 55 13 2 61 10 2
  Nausea 43 4 - 51 3 < 1
  Vomiting 27 4 < 1 30 4 < 1
  Stomatitis 25 2 < 1 62 14 1
  Abdominal Pain 35 9 < 1 31 5 -
  Gastrointestinal Motility Disorder 10 < 1 - 7 < 1 -
  Constipation 14 1 < 1 17 1 -
  Oral Discomfort 10 - - 10 - -
  Upper GI Inflammatory Disorders 8 < 1 - 10 1 -
  Gastrointestinal Hemorrhage 6 1 < 1 3 1 -
  Ileus 6 4 1 5 2 1
Skin and Subcutaneous
  Hand-and-Foot Syndrome 54 17 NA 6 1 NA
  Dermatitis 27 1 - 26 1 -
  Skin Discoloration 7 < 1 - 5 - -
  Alopecia 6 - - 21 < 1 -
General
  Fatigue/Weakness 42 4 - 46 4 -
  Pyrexia 18 1 - 21 2 -
  Edema 15 1 - 9 1 -
  Pain 12 1 - 10 1 -
  Chest Pain 6 1 - 6 1 < 1
Neurological
  Peripheral Sensory Neuropathy 10 - - 4 - -
  Headache 10 1 - 7 - -
  Dizziness* 8 < 1 - 8 < 1 -
  Insomnia 7 - - 7 - -
  Taste Disturbance 6 1 - 11 < 1 1
Metabolism
  Appetite Decreased 26 3 < 1 31 2 < 1
  Dehydration 7 2 < 1 8 3 1
Eye
  Eye Irritation 13 - - 10 < 1 -
  Vision Abnormal 5 - - 2 - -
Respiratory
  Dyspnea 14 1 - 10 < 1 1
  Cough 7 < 1 1 8 - -
  Pharyngeal Disorder 5 - - 5 - -
  Epistaxis 3 < 1 - 6 - -
  Sore Throat 2 - - 6 - -
Musculoskeletal
  Back Pain 10 2 - 9 < 1 -
  Arthralgia 8 1 - 6 1 -
Vascular
  Venous Thrombosis 8 3 < 1 6 2 -
Psychiatric
  Mood Alteration 5 - - 6 < 1 -
  Depression 5 - - 4 < 1 -
Infections
  Viral 5 < 1 - 5 < 1 -
Blood and Lymphatic
  Anemia 80 2 < 1 79 1 < 1
  Neutropenia 13 1 2 46 8 13
Hepatobiliary
  Hyperbilirubinemia 48 18 5 17 3 3
– Not observed
* Excluding vertigo
NA = Not Applicable

Breast Cancer

In Combination with Docetaxel

The following data are shown for the combination study with XELODA and docetaxel in patients with metastatic breast cancer in Table 7 and Table 8. In the XELODA and docetaxel combination arm the treatment was XELODA administered orally 1250 mg/m² twice daily as intermittent therapy (2 weeks of treatment followed by 1 week without treatment) for at least 6 weeks and docetaxel administered as a 1-hour intravenous infusion at a dose of 75 mg/m² on the first day of each 3-week cycle for at least 6 weeks. In the monotherapy arm docetaxel was administered as a 1-hour intravenous infusion at a dose of 100 mg/m² on the first day of each 3week cycle for at least 6 weeks. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (19%) in the monotherapy arm withdrew from the study because of adverse reactions. The percentage of patients requiring dose reductions due to adverse reactions was 65% in the combination arm and 36% in the monotherapy arm. The percentage of patients requiring treatment interruptions due to adverse reactions in the combination arm was 79%. Treatment interruptions were part of the dose modification scheme for the combination therapy arm but not for the docetaxel monotherapy-treated patients.

Table 7 Percent Incidence of Adverse Events Considered Related or Unrelated to Treatment in ≥ 5% of Patients Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study


– Not observed NA = Not Applicable
Adverse Event XELODA 1250 mg/m²/bid With Docetaxel 75 mg/m²/3 weeks (n=251) Docetaxel 100 mg/m²/3 weeks (n=255)
Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 %
Number of Patients With at Least One Adverse Event 99 76.5 29.1 97 57.6 31.8
Body System/Adverse Event
GI
  Diarrhea 67 14 < 1 48 5 < 1
  Stomatitis 67 17 < 1 43 5 -
  Nausea 45 7 - 36 2 -
  Vomiting 35 4 1 24 2 -
  Constipation 20 2 - 18 - -
  Abdominal Pain 30 < 3 < 1 24 2 -
  Dyspepsia 14 - - 8 1 -
  Dry Mouth 6 < 1 - 5 - -
Skin and Subcutaneous
  Hand-and-Foot Syndrome 63 24 NA 8 1 NA
  Alopecia 41 6 - 42 7 -
  Nail Disorder 14 2 - 15 - -
  Dermatitis 8 - - 11 1 -
  Rash Erythematous 9 < 1 - 5 - -
  Nail Discoloration 6 - - 4 < 1 -
  Onycholysis 5 1 - 5 1 -
  Pruritus 4 - - 5 - -
General
  Pyrexia 28 2 - 34 2 -
 Asthenia 26 4 < 1 25 6 -
  Fatigue 22 4 - 27 6 -
  Weakness 16 2 - 11 2 -
  Pain in Limb 13 < 1 - 13 2 -
  Lethargy 7 - - 6 2 -
  Pain 7 < 1 - 5 1 -
  Chest Pain (non-cardiac) 4 < 1 - 6 2 -
  Influenza-like Illness 5 - - 5 - -
Neurological
  Taste Disturbance 16 < 1 - 14 < 1 -
  Headache 15 3 - 15 2 -
  Paresthesia 12 < 1 - 16 1 -
  Dizziness 12 - - 8 < 1 -
  Insomnia 8 - - 10 < 1 -
  Peripheral Neuropathy 6 - - 10 1 -
  Hypoaesthesia 4 < 1 - 8 < 1 -
Metabolism
  Anorexia 13 1 - 11 < 1 -
  Appetite Decreased 10 - - 5 - -
  Weight Decreased 7 - - 5 - -
  Dehydration 10 2 - 7 < 1 < 1
Eye
  Lacrimation Increased 12 - - 7 < 1 -
  Conjunctivitis 5 - - 4 - -
  Eye Irritation 5 - - 1 - -
Musculoskeletal
  Arthralgia 15 2 - 24 3 -
  Myalgia 15 2 - 25 2 -
  Back Pain 12 < 1 - 11 3 -
  Bone Pain 8 < 1 - 10 2 -
Cardiac
  Edema 33 < 2 - 34 < 3 1
Blood
  Neutropenic Fever 16 3 13 21 5 16
Respiratory
  Dyspnea 14 2 < 1 16 2 -
  Cough 13 1 - 22 < 1 -
  Sore Throat 12 2 - 11 < 1 -
  Epistaxis 7 < 1 - 6 - -
  Rhinorrhea 5 - - 3 - -
  Pleural Effusion 2 1 - 7 4 -
Infection
  Oral Candidiasis  7 < 1 - 8 < 1 -
  Urinary Tract Infection 6 < 1 - 4 - -
  Upper Respiratory Tract 4 - - 5 1 -
Vascular
  Flushing 5 - - 5 - -
  Lymphoedema 3 < 1 - 5 1 -
Psychiatric
  Depression 5 - - 5 1 -

Table 8 : Percent of Patients With Laboratory Abnormalities Participating in the XELODA and Docetaxel Combination vs Docetaxel Monotherapy Study

Adverse Event XELODA 1250 mg/m²/bid With Docetaxel 75 mg/m²/3 weeks (n=251) Docetaxel 100 mg/m²/3 weeks (n=255)
Body System/Adverse Event Total % Grade 3 % Grade 4 % Total % Grade 3 % Grade 4 %
Hematologic
  Leukopenia 91 37 24 88 42 33
  Neutropenia/ Granulocytopenia 86 20 49 87 10 66
  Thrombocytopenia 41 2 1 23 1 2
  Anemia 80 7 3 83 5 < 1
  Lymphocytopenia 99 48 41 98 44 40
Hepatobiliary
  Hyperbilirubinemia 20 7 2 6 2 2

Monotherapy

The following data are shown for the study in stage IV breast cancer patients who received a dose of 1250 mg/m² administered twice daily for 2 weeks followed by a 1-week rest period. The mean duration of treatment was 114 days. A total of 13 out of 162 patients (8%) discontinued treatment because of adverse reactions/intercurrent illness.

Table 9 : Percent Incidence of Adverse Reactions Considered Remotely, Possibly or Probably Related to Treatment in ≥ 5% of Patients Participating in the Single Arm Trial in Stage IV Breast Cancer

Adverse Event Phase 2 Trial in Stage IV Breast Cancer
(n=162)
Body System/Adverse Event Total % Grade 3 % Grade 4 %
GI
  Diarrhea 57 12 3
  Nausea 53 4 -
  Vomiting 37 4 -
  Stomatitis 24 7 -
  Abdominal Pain 20 4 -
  Constipation 15 1 -
  Dyspepsia 8 - -
Skin and Subcutaneous
  Hand-and-Foot Syndrome 57 11 NA
  Dermatitis 37 1 -
  Nail Disorder 7 - -
General
  Fatigue 41 8 -
  Pyrexia 12 1 -
  Pain in Limb 6 1 -
Neurological
  Paresthesia 21 1 -
  Headache 9 1 -
  Dizziness 8 - -
  Insomnia 8 - -
Metabolism
  Anorexia 23 3 -
  Dehydration 7 4 1
Eye
  Eye Irritation 15 - -
Musculoskeletal
  Myalgia 9 - -
  Cardiac Edema 9 1
Blood
  Neutropenia 26 2 2
  Thrombocytopenia 24 3 1
  Anemia 72 3 1
  Lymphopenia 94 44 15
Hepatobiliary
  Hyperbilirubinemia 22 9 2
– Not observed
NA = Not Applicable

Clinically Relevant Adverse Events In < 5% Of Patients

Clinically relevant adverse events reported in < 5% of patients treated with XELODA either as monotherapy or in combination with docetaxol that were considered at least remotely related to treatment are shown below; occurrences of each grade 3 and 4 adverse event are provided in parentheses.

Monotherapy (Metastatic Colorectal Cancer, Adjuvant Colorectal Cancer, Metastatic Breast Cancer)

Gastrointestinal: abdominal distension, dysphagia, proctalgia, ascites (0.1%), gastric ulcer (0.1%), ileus (0.3%), toxic dilation of intestine, gastroenteritis (0.1%)

Skin & Subcutan.: nail disorder (0.1%), sweating increased (0.1%), photosensitivity reaction (0.1%), skin ulceration, pruritus, radiation recall syndrome (0.2%)

General: chest pain (0.2%), influenza-like illness, hot flushes, pain (0.1%), hoarseness, irritability, difficulty in walking, thirst, chest mass, collapse, fibrosis (0.1%), hemorrhage, edema, sedation

Neurological: insomnia, ataxia (0.5%), tremor, dysphasia, encephalopathy (0.1%), abnormal coordination, dysarthria, loss of consciousness (0.2%), impaired balance

Metabolism: increased weight, cachexia (0.4%), hypertriglyceridemia (0.1%), hypokalemia, hypomagnesemia

Eye: conjunctivitis

Respiratory: cough (0.1%), epistaxis (0.1%), asthma (0.2%), hemoptysis, respiratory distress (0.1%), dyspnea

Cardiac: tachycardia (0.1%), bradycardia, atrial fibrillation, ventricular extrasystoles, extrasystoles, myocarditis (0.1%), pericardial effusion

Infections: laryngitis (1.0%), bronchitis (0.2%), pneumonia (0.2%), bronchopneumonia (0.2%), keratoconjunctivitis, sepsis (0.3%), fungal infections (including candidiasis) (0.2%)

Musculoskeletal: myalgia, bone pain (0.1%), arthritis (0.1%), muscle weakness

Blood & Lymphatic: leukopenia (0.2%), coagulation disorder (0.1%), bone marrow depression (0.1%), idiopathic thrombocytopenia purpura (1.0%), pancytopenia (0.1%)

Vascular: hypotension (0.2%), hypertension (0.1%), lymphoedema (0.1%), pulmonary embolism (0.2%), cerebrovascular accident (0.1%)

Psychiatric: depression, confusion (0.1%)

Renal: renal impairment (0.6%)

Ear: vertigo

Hepatobiliary: hepatic fibrosis (0.1%), hepatitis (0.1%), cholestatic hepatitis (0.1%), abnormal liver function tests

Immune System: drug hypersensitivity (0.1%)

Postmarketing: hepatic failure, lacrimal duct stenosis, acute renal failure secondary to dehydration including fatal outcome [see WARNINGS AND PRECAUTIONS], cutaneous lupus erythematosus, corneal disorders including keratitis, severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (TEN) [see WARNINGS AND PRECAUTIONS]

XELODA In Combination With Docetaxel (Metastatic Breast Cancer)

Gastrointestinal: ileus (0.4%), necrotizing enterocolitis (0.4%), esophageal ulcer (0.4%), hemorrhagic diarrhea (0.8%)

Neurological: ataxia (0.4%), syncope (1.2%), taste loss (0.8%), polyneuropathy (0.4%), migraine (0.4%)

Cardiac: supraventricular tachycardia (0.4%)

Infection: neutropenic sepsis (2.4%), sepsis (0.4%), bronchopneumonia (0.4%)

Blood & Lymphatic: agranulocytosis (0.4%), prothrombin decreased (0.4%)

Vascular: hypotension (1.2%), venous phlebitis and thrombophlebitis (0.4%), postural hypotension (0.8%)

Renal: renal failure (0.4%)

Hepatobiliary: jaundice (0.4%), abnormal liver function tests (0.4%), hepatic failure (0.4%), hepatic coma (0.4%), hepatotoxicity (0.4%)

Immune System: hypersensitivity (1.2%)